Extraction selectivities of lower rim substituted calix[4]arene hosts induced by variations in the upper rim substituents

The compound 25,26,27,28-tetra-(2-dimethyldithiocarbamoylethoxy)calix[4]arene has been prepared from 25,26,27,28-tetra-(2-bromoethoxy)calix[4]arene by reaction with sodium dimethyldithiocarbamate. As an extractant for heavy metal ions 25,26,27,28-tetra-(2-dimethyldithiocarbamoylethoxy)calix[4]arene is effective for Hg²⁺, Ag⁺, Pd²⁺ and Au³⁺, but much less effective than 5,11,17,23-tetra-tert-butyl-25,26,27,28-tetra-(2-N,N-dimethyldithiocarbamoylethoxy)calix[4]arene for both Hg₂²⁺ and MeHg⁺. Calixarene alcohols also show selectivity as hosts. The alcohol derivative 25,26,27,28-tetra-(2-hydroxyethoxy)calix[4]arene undergoes slow occlusion of iodine into the lower rim, whereas with the alcohol 5,11,17,23-tetra-tert-butyl-25,26,27,28-tetra-(2-hydroxyethoxy)calix[4]arene no interaction is observed.     

Synthesis of calix[n]arene-based silica polymers for lipase immobilization

The objective of this study was to prepare new calix[n]arene-based silica polymers for immobilization of Candida rugosa lipase. The amino functionalized calix[4]arene (C4P), calix[6]arene (C6P) and calix[8]arene (C8P)-based silica polymers were used for the covalent attachment of C. rugosa lipase using glutaraldehyde as a coupling agent. The characterization of synthesized CnP polymers and immobilized lipases were made by Fourier transform infrared spectroscopy (FTIR), thermal gravimetric analysis (TGA) and scanning electron microscope (SEM) techniques. The hydrolytic activities of immobilized lipases (CnP-L) were evaluated and compared with the free enzyme. The activity recovery of immobilized CRL (C. rugosa lipase) based on the carrier C4P, C6P and C8P reaches 74.6%, 68.5% and 51.4%, respectively. The optimal pH and temperature region of the immobilized lipases for the hydrolysis of p-NPP were 7.0 and 50 °C. Nevertheless, the immobilized lipase has good stability, adaptability and reusability in comparison with the free enzyme.     

Modelling of auxetic networked polymers built from calix[4]arene building blocks

Auxetic materials (i.e. materials with a negative Poisson's ratio) expand laterally when stretched and become thinner when compressed. This unusual yet very useful property arises from the way by which the nano or microstructure of the material deforms when subjected to uniaxial mechanical loads. This paper discusses a novel class of molecular-level auxetic (networked polymers) built from calix[4]arene building blocks. These calix[4]arene subunits are connected in such a way that they mimic the shape of a “folded macrostructure” which is known to exhibit auxetic behaviour. We confirm through force-field based simulations that these newly proposed networked polymers exhibit negative Poisson's ratios, the magnitudes of which can be changed by introducing slight variations in the molecular structure of these polymers. We also develop simple geometry-based models which explain the values of the Poisson's ratios obtained through the force-field based simulations, and which give an insight into the features of the molecular structure that are responsible for the auxetic effect.     

Modulation of cell proliferation in rat liver cell cultures by new calix[4]arenes

Cell cycle progression is dependent on intracellular iron level and chelators lead to iron depletion and decrease cell proliferation. This antiproliferative effect can be inhibited by exogenous iron. In this work, we present the synthesis of new synthetic calix[4]arene podands bearing two aspartic/glutamic acid, ornithine groups or hydrazide function at the lower rim, designed as potential iron chelators. The synthesis only afforded calix[4]arenes in the cone conformation. We report their effect on cell proliferation, in comparison with the new oral chelator ICL670A (4-[3,5-bis-(2-hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid). The antiproliferative effect of these new compounds was studied in the rat hepatoma cell line Fao by measuring mitochondrial succinate dehydrogenase activity. Their cytotoxicity was evaluated by extracellular LDH activity. Preliminary results indicated that among all tested compounds, monohydrazidocalix[4]arene 2 which is not cytotoxic in Fao cells exhibits interesting antiproliferative activity. This effect, independent on iron depletion, remains to be further explored. Moreover, it also shows that new substituted calix[4]arenes could open the way to new valuable medicinal chemistry scaffolding.     

Structural and functional bases of the intermolecular interaction of calix[4]arene C-97 with myosin subfragment-1 of myometrium

Calix[4]arene C-97 (code is shown) is the macrocyclic compound which has lipophilic intramolecular higly-structured cavity formed by four aromatic cycles, one of which on the upper rim is modified by methylene bisphosphonic group. It was shown that calix[4]arene C-97 (100 microM) efficiently inhibits ATPase activity of myosin subfragment-1 from pig myometrium, the inhibition coefficient I(0.5) being 83 +/- 7 microM. At the same time, this compound at 100 microM concentration significantly increases the effective hydrodynamic diameter of myosin subfragment-1, that may be indicative of intermolecular complexation between the calix[4]arene and myosin head. Computer simulation methods (docking, molecular dynamics, involving the Grid) have been used to clarify structural basis of the intermolecular interaction of calix[4]arene C-97 with myosin subfragment-1 of the myometrium; participation of hydrophobic, electrostatic and pi-pi (stacking) interactions between calix[4]arene C-97 and amino acid residues of myosin subfragment-1, some of them being located near the active site of the ATPase has been found out.     

Kinetic regularities and mechanisms of action of calix[4]arene C-99 on ATPase activity of myosin subfragment-1 of myometrium

It has been shown that calix[4]arene C-99 inhibited myosin subfragment-1 ATPase of myometrium. This inhibition is noncompetitive as to ATP and Mg2+. At the same time, this compound reduces the seeming enzymatic hydrolysis maximum rate of nucleoside triphosphate with respect to ATP and Mg2+. With the help of computer design the interaction of mentioned calix[4]arene with myosin subfragment-1 of myometrium has been investigated. Several mechanisms involved in the calix[4]arene C-99 inhibition of myosin head ATPase were supposed and participation of hydrogen, hydrophobic and electrostatic interactions in these mechanisms was discussed.     

Calix[4]arenes C-136 and C-137 hyperpolarize myometrium mitochondria membranes

Calixarenes are supramolecular compounds interacting with bioactive molecules and ions, causing changes in biochemical and biophysical processes. The aim of this work was to study the effects of calix[4]arenes C-136, C-137, and C-138 at the level of polarization of the rat myometrium mitochondria membrane. The structure of synthesized calix[4]arene molecules was confirmed by the methods of ¹H NMR and infrared spectroscopy. Calix[4]arenes C-136 and C-137 each possess two chalcone amide moieties at the lower rim, while calix[4]arene C-138, only one. Calix[4]arenes C-136 and C-137 differ by the presence of ether or hydroxyl groups, respectively, at the lower rim of calix[4]arene skeleton, as well as the length of alkyl spacer between chalcone amide group and the macrocycle. It was shown that calix[4]arenes C-136, C-137, and C-138 form micelles in aqueous medium and in dimethylformamide (DMF). Irradiation of micelles with an argon laser on the flow cytometer results in the rise of autofluorescence. In an aqueous medium, calix[4]arene micelles interact with a positively charged voltage-sensitive fluorescent probe TMRM, which can testify to the presence of negative charge in these structures. However, calix[4]arene micelles do not interact with TMRM in DMF solution. The mitochondrial membrane potential was measured using fluorescent dyes MTG and TMRM with confocal microscopy and fluorescent dye TMRM with flow cytometry. Experiments were conducted on myometrium cells in culture and on suspension of digitonin-permeabilized uterus myocytes. It was shown that the fluorescent signal was stable during the time of experiment. Calix[4]arenes C-136 and C-137 (10 μM) hyperpolarize mitochondria membranes. At maximum, the effect was 173% relative to the control. At the same time, calix[4]arene C-138 did not influence the mitochondria membrane potential. The relationship between the structural organization of investigated calix[4]arene molecules and their effect on polarization of the mitochondria membrane is discussed.     

Electronic absorption spectroscopy for the investigation of the solution binding of gold, palladium, mercury and silver salts to the lower rim substituted calix[4]arenes 25,26,27,28-(2-N,N-dimethyldithiocarbamoylethoxy)calix[4]arene and 25,26,27,28-(2-methylthioethoxy)calix[4]arene

The two uncharged compounds 25,26,27,28-(2-N,N-di methyldithiocarbamoylethoxy)calix[4]arene (1) and 25,26,27,28- (2-methylthioethoxy)calix[4]arene (2) are effective extractants for transferring Hg(II), Ag(I), Pd(II) and Au(III) from aqueous solution into chloroform. The electronic absorption spectra of 1 and 2 show additional bands at long wavelength upon complexation with AuCl₄⁻, PdCl₄²⁻ and PdBr₄²⁻, and analogous bands for Hg²⁺ and Ag⁺ with 1. For 1 these new bands are considered to be either of the charge transfer type or transitions within the C=S moiety. These new bands for the complexes with 2 are assigned to LMCT transitions of the S → M type. These spectral features are used to obtain information about the solution structures of the complexes that are formed between these metal ions and both 1 and 2.     

Unusual reactivity of copper(I) complexes of functionalised calix[4]arenes

Two functionalised calix[4]arenes, 5,11,17,23-tetra-tert-butyl-25,27-bis(2-pyridylmethoxy)calix[4]arene (L¹) and 5,11,17,23-tetra-tert-butyl-25,27-bis(2-pyridylmethoxy)-26,28-dibutoxycalix[4]arene (L³), were prepared and characterised. The copper(I) complexes of both calix[4]arenes were synthesised and their reactivities were analysed and compared. The presence of the metal induced a radical in the case of L¹ whereas no such radical was observed in the metal complex of ligand L³.     

Chiral calix[4]arenes bearing amino alcohol functionality as membrane carriers for transport of chiral amino acid methylesters and mandelic acid

Novel chiral calix[4]arene derivatives bearing amino alcohol moieties at the lower rim have been synthesized from the reaction of p-tert-butylcalix[4]arene diester with various amino alcohols. The transport of amino acid esters (phenylglycine, phenylalanine, and tryptophan methyl esters hydrochloride) and mandelic acid were studied through chloroform bulk liquid membrane system using chiral calix[4]arenes 15-20. All these receptors have been found to act as carriers for transport of aromatic amino acid methylesters and mandelic acid from the aqueous source phase to the aqueous receiving phase. The influence of calixarene and guest structures upon transport through liquid membrane is discussed.     

Synthesis and structural analysis of calix[4]arene-supported iron(III) complexes

The paper describes the reactivity of calix[4]arene dialkyl- or -silylethers H₂R₂calix, R=Me (1), Bz (2), or SiMe₃ (3) (p-tert.butyl-calix[4]arene=H₄calix), towards the iron(III) complex [FeCl(NSiMe₃)₂(thf)] 4. Bis(silylation) of H₄calix was achieved using a mixture of NEt₃ and Me₃SiCl as silylating agent, which is probably the most convenient and cheapest way for the preparation of H₂(Me₃Si)₂calix 3. [FeCl(N{SiMe₃}₂)₂(thf)] 4 has been obtained from the reaction of [FeCl₃] and commercially available K[N(SiMe₃)₂] in THF. The reactions of 4 with H₂Me₂calix and H₂Bz₂calix afford mononuclear iron(III) chloro compounds [FeCl(R₂calix)] 5 (R=Me) and 6 (R=Bz). The usage of calix[4]arene silyl ether 3 leads to a dinuclear complex [Fe₂({Me₃Si}calix)₂] 7, presumably under Me₃SiCl cleavage of a mononuclear calixarene iron(III) chloro complex. The calix[4]arene ether stabilized iron(III) chloro complexes are susceptible to nucleophilic substitution reactions, as exemplified by the reaction of 5 with sodium azide yielding an azido complex [Fe(N₃)(Me₂calix)] 8. The molecular structures of 4, 5, 6, 7, and 8 in the solid state have been determined by X-ray diffraction.     

Calix[4]arene C-90 selectively inhibits Ca2+,Mg2+-ATPase of myometrium cell plasma membrane

The supramolecular compound calix[4]arene C-90 (5,11,17,23-tetra(trifluoro)methyl(phenylsulfonylimino)-methylamino-25,26,27,28-tetrapropoxycalix[4]arene) is shown to efficiently inhibit the ATP hydrolase activity of Ca²⁺,Mg²⁺-ATPase in the myometrium cell plasma membrane fraction and also in a preparation of the purified enzyme solubilized from this subcellular fraction. The inhibition coefficient I _0.5 values were 20.2 ± 0.5 and 58.5 ± 6.4 μM for the membrane fraction and the solubilized enzyme, respectively. The inhibitory effect of calix[4]arene C-90 was selective comparatively to other ATPases localized in the plasma membrane: calix[4]arene C-90 did not influence the activities of Na⁺,K⁺-ATPase and “basal” Mg²⁺-ATPase. The inhibitory effect of calix[4]arene C-90 on the Ca²⁺,Mg²⁺-ATPase activity was associated with the cooperative action of four trifluoromethylphenyl sulfonylimine (sulfonylamidine) groups oriented similarly on the upper rim of the calix[4]arene macrocycle (the calix[4]arene “bowl”). The experimental findings seem to be of importance for studies, using calix[4]arene C-90, of membrane mechanisms of regulation of calcium homeostasis in smooth muscle cells and also for investigation of the participation of the plasma membrane Ca²⁺-pump in control of electro- and pharmacomechanical coupling in myocytes.     

Chiral mono and diamide derivatives of calix[4]arene for enantiomeric recognition of chiral amines

Novel chiral mono and diamide derivatives of calix[4]arene have been prepared from the aminolysis reaction of 5,11,17,23-tetra-tert-butyl-25,27-diethoxycarbonyl-methoxy-26,28-dihydroxycalix[4]arene 1 and 25,27-diethoxycarbonyl-methoxy-26,28-dihydroxycalix[4]arene 2 with chiral (S)-(-)-1-phenylethylamine (PEA) and (1S,2S)-(+)-2-amino-1-(4-nitrophenyl)-1,3-propanediol, respectively. Spectrophotometric titrations have been performed in CHCl(3) at 20-30 degrees C in order to obtain the binding constants (K) and the thermodynamic quantities (DeltaH and DeltaS) for the stoichiometric 1:1 inclusion complexation of various chiral amines with these new host compounds. Preliminary experiments were undertaken to confirm the complexation properties of receptors 9 and 13 with PEA by (1)H NMR in CDCl(3) at room temperature. The molecular recognition abilities and enantioselectivities for guests (R and S)-alpha-PEA and (R and S)-cyclohexylethylamine (CHEA) are discussed from a thermodynamic point of view.     

New strapped calix[4]pyrrole based receptor for anions

Calix[4]pyrrole bearing catechol-derived diether strap linked via alkyl chains has been synthesized and characterized for the first time. The strap with 1,2-diether link is providing a relatively constrained geometry on its side of the calix[4]pyrrole moiety. As a result only one isomer (cis-type) of the receptor formed during reaction. The crystal structure reveals two molecules of methanol bound to the host. This calix[4]pyrrole also exhibits enhanced binding towards halide anions compared to simple calix[4]pyrrole apart from showing binding towards dihydrogenphosphate and acetate ions. The association constants are quite similar to that found for orcinol strapped calix[4]pyrrole towards halide anions in general, but having a higher preference for chloride than bromide ion in particular. Further it shows very strong preference towards fluoride ion.     

Calix[4]arene decorated with four Tn antigen glycomimetic units and P3CS immunoadjuvant: synthesis, characterization, and anticancer immunological evaluation

A novel anticancer vaccine candidate built on a nonpeptidic scaffold has been synthesized. Four S-Tn tumor-associated glycomimetic antigens have been clustered onto a calix[4]arene scaffold bearing an immunoadjuvant moiety (P3CS). The immunogenicity of the synthetic construct has been investigated by immunization of mice in vivo. ELISA assay has evidenced that the tetravalent construct stimulates a higher production of anti-Tn antigen IgG antibodies when compared to an analogous monovalent compound. This result is ascribable to an antigen cluster effect and makes the reported vaccine candidate a good mimic of the natural motifs present on the mucine surface.     

Calix[4]arene methylenebisphosphonic acids: the features of alkaline phosphatases inhibition

The inhibition of alkaline phosphatases by calix[4]arenes functionalysed at the macrocyclic upper rim by one or two methylenebisphosphonic acid fragments has been investigated. It is established, that calix[4]arene bismethylenebisphosphonic acid displayed stronger inhibition of alkaline phosphatase from bovine intestine mucosa than calix[4]arene methylenebisphosphonic acid. At the same time, the both inhibitors showed almost similar levels of inhibitory activities in respect of bovine kidney alkaline phosphatase or E. coli alkaline phosphatase. The tested compounds were docked computationally to the active site of the E. coli alkaline phosphatase. On the basis of results obtained the possible binding modes of inhibitors were analysed.     

Stereodesign of chiral para-substituted calix[4]arenes

According to the hypothesis that the chirality of molecule hosts is a cause of their enantioselectivity, the chirality of para-substituted calix[4]arenes was analyzed quantitatively. The relationship between types of para-substituents and the dissymmetry of the 2D (two-dimensional) entrance into the cavity and the whole 3D (three-dimensional) cavity of calix[4]arenes was studied by means of the enantiomer dissimilarity factor (EDF) method for quantitative evaluation of molecular chirality. The design of the most chiral, and probably enantioselective, para-substituted calix[4]arenes was planned such that all four substituents should be different and the two largest should be near each other (adjacent). It was, on the other hand, shown that the 2D chiral entrance determines chirality of the whole 3D structures of these molecules. This phenomenon is interpreted as an example of the chirality transition from 2D into 3D space.Electronic Supplementary Material available.     

Antiproliferative effect on HepaRG cell cultures of new calix[4]arenes

Cell cycle progression is dependent on the intracellular iron level, and chelators lead to iron depletion and decrease cell proliferation. This antiproliferative effect can be inhibited by exogenous iron. In this work, we present the synthesis of new synthetic calix[4]arene podands bearing alkyl acid and alkyl ester groups at the lower rim, designed as potential iron chelators. We report their effect on cell proliferation, in comparison with the new oral chelator ICL670 (4-[3,5-bis-(2-hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid). The antiproliferative effect of these new compounds was studied in human hepatocarcinoma HepaRG cell cultures using the MTT assay. Their cytotoxicity was evaluated by extracellular LDH activity. Preliminary results indicate that their antiproliferative effect is due to their cytotoxicity. The efficiency of these compounds, comparable to that of ICL670, was independent of iron depletion. This effect remains to be further explored. Moreover, it also shows that novel substituted calix[4]arenes could open the way to new valuable medicinal chemistry scaffolding.     

Solvent extraction of divalent palladium and platinum from aqueous solutions of their chloro complexes using an N,N-dimethyldithiocarbamoylethoxy substituted calix[4]arene

The compound 5,11,17,23-tetra-tert-butyl-25,26,27,28-tetra-(2-bromoethoxy)calix[4]arene has been prepared by first converting 5,11,17,23-tetra-tert-butyl-25,26,27,28-tetra-(2-hydroxyethoxy)calix[4]arene into the tosylate, and then to the product by reaction with LiBr. The compound crystallizes in the trigonal space group P3₂21 with A = 13.160(2), C = 25.595(6) Å, A = 90.00(2), β = 90.00(1), γ = 120.000(9)⁰, Z = 3, _calc = 1.40 g cm⁻³. The final R value for 2391 unique reflections was 0.061. The compound reacts with excess sodium N,N-dimethyldithiocarbamate to give 5,11,17,23-tetra-tert-butyl-25,26,27,28-tetra-(2-N,N-dimethyldithiocarbamoylethoxy)calix[4]arene. This compound is an effective extractant for transferring palladium(II) from an aqueous to a chloroform phase. No extraction of PtCl₄²⁻ is observed under thermal conditions. Under photochemical conditions using a mixture of PtCl₄²⁻ and PtCl₆²⁻, extraction of platinum into the chloroform layer is observed. An explanation for this observation is given.     

Synthesis and complexation of tetrakis(diphenylphosphinomethyl)calix[4]arene adopting the 1,3-alternate conformation

Novel upper-rim modified tetraphosphinocalix[4]arenes (5a-b) adopting 1,3-alternate conformation have been synthesized. Reaction of 5,11,17,23-tetrachloromethyl-25,26,27,28-tetrahydroxycalix[4]arene (1) with Ph₂POEt gave 5,11,17,23-tetrakis(diphenylphosphinoylmethyl)-25,26,27,28-tetrahydroxycalix[4]arene (2). Tetra-O-substitution of 2 with n-propyl iodide or benzyl bromide in the presence of K₂CO₃ carried out to afford 5,11,17,23-tetrakis(diphenylphosphinoylmethyl)-25,26,27,28-tetrapropoxy-(3a) or -benzyloxycalix[4]arene (3b), whereas di-O-substituted calix[4]arene, 5,11,17,23-tetrakis(diphenylphosphinoylmethyl)-25,27-dipropoxy-26,28-dihydroxycalix[4]arene (4), was obtained exclusively when Na₂CO₃ was used as base. Reduction of 3a-b with PhSiHCl₂ afforded 5,11,17,23-tetrakis(diphosphinomethyl)-25,26,27,28-tetrapropoxy-(5a) and -tetrabenzyloxycalix[4]arene (5b). ¹H and ¹³C NMR analysis reveals that the phosphines (5a-b) and the tetra-O-substituted phosphine oxides (3a-b) adopt 1,3-alternate conformation, while the parent tetrahydroxy-(2) and the di-O-propylated phosphine oxide (4) adopt cone-conformation. The X-ray structure indicates that the calix[4]arene moieties in 4 a pinched-cone conformation in solid state. Complexation of the phosphine ligand (5a) with [RuCl₂(p-cymene)]₂ affords the tetranuclear complexes, [{RuCl₂(p-cymene)}₂ · 5a] (6), as 1,3-alternate conformer.